Current use of azithromycin (Zithromax/Zmax, Pfizer) was linked with a twofold increased risk of ventricular arrhythmia compared with no antibiotic use, but this risk disappeared when azithromycin use was compared with amoxicillin use, in a large European study.
These findings from more than 14 million outpatients in five European countries who were part of the Arrhythmogenic Potential of Drugs (ARITMO) study were published April 18, 2017 in CMAJ.
The results suggest that "the risk of ventricular arrhythmia with azithromycin use is likely to be mainly due to the poor state of health [of the patient] due to the underlying infection rather than [due to] the drug itself," Dr Gianluca Trifirò (Erasmus University Medical Center, Rotterdam, the Netherlands and University of Messina, Italy) told heartwire from Medscape in an email.
The "risk of ventricular arrhythmia with azithromycin is likely to be negligible compared with other antibiotics, [although] high-risk patients, such as very old and very young patients, those with preexisting heart conditions, and so on, should be carefully monitored when taking any antibiotics," he continued.
Asked about the 2013 safety warning from the US Food and Drug Administration stating that azithhromycin poses a risk for potentially fatal arrhythmia in certain patients, largely based on a 2012 study, he replied: "Perhaps the FDA wanted to take a conservative and cautious approach in issuing a warning on the risk of heart-rhythm disorders with azithromycin, which at the time was alarming news, considering how widely used this drug is."
It is quite conceivable that the increased cardiovascular risk from azithromycin for the US Medicaid population that was investigated in the study that prompted the FDA warning "remains valid for that particular population, [whereas] it is not as high for other populations," he observed. "Our results suggest this excess risk would be negligible in a European [outpatient] population. "
Azithromycin and Arrhythmia Risk in the European Community
There are conflicting results from large epidemiologic studies that looked at the risk of cardiovascular death and, more rarely, cardiac arrhythmia in patients who received azithromycin, according to Trifirò and colleagues.
To determine the risk of ventricular arrhythmia with azithromycin use, they analyzed data from the ARMITO study of more than 28 million patients in seven population-based databases in Denmark, Germany, Italy, the Netherlands, and the United Kingdom, from 1997 to 2010.
The researchers identified 14 million adult patients up to age 85 who had received a new prescription for an antibiotic (mostly from a general practitioner) typically for a respiratory or urinary-tract infection. Patients were excluded if they had been taking an antibiotic in the previous year, had cancer, or had been admitted to the hospital.
Of these patients, 12,874 patients developed ventricular arrhythmia, and each case was matched with 100 control patients from the same database with the same age (within a year), sex, and date of initial antibiotic prescription.
Patients in the two groups (cases and controls) had a mean age 64; a third were younger than 60; 55% were 60 to 79; and 12% were 80 to 85 years old. Two-thirds were men.
Compared with the controls, the patients who developed ventricular arrhythmia were significantly more likely to have atrial fibrillation, cardiomyopathy, coronary artery disease, electrolyte imbalance, hypertension, peripheral arterial disease, prior use of antiarrhythmic drugs, chronic respiratory disease, diabetes, obesity, or lipid-metabolism disorders or be taking medications that can induce hypokalemia or prolong the QT interval.
Of the patients who developed ventricular arrhythmia, 1221 were current users of azithromycin (30 patients), amoxicillin (165 patients), or another antibiotic (1026 patients).
Current azithromycin use was associated with an increased risk of ventricular arrhythmia compared with no antibiotic use, but not compared with amoxicillin use, after adjustment for multiple confounders, in a pooled analysis.
Risk of Ventricular Arrhythmia, Current Azithromycin Use vs Amoxicillin Use or No Antibiotic Usea
|Current use||Adjusted HR (95% CI)b|
|Azithromycin vs amoxicillin||0.94 (0.50–1.77)|
|Azithromycin vs no antibiotic||1.97 (1.35–2.86)|
a. Pooled analysis across seven databases
b. Adjusted for atrial fibrillation/flutter, cardiomyopathy, coronary artery disease, cerebrovascular disorders, chronic obstructive pulmonary disease, electrolytic imbalance, heart failure, hypertension, type 2 diabetes, lipid disorder, peripheral arterial disease, hypothyroidism, prior use of antiarrhythmic drugs, and concomitant use of drugs known to cause hypokalemia or prolong the QT interval
The findings were similar in separate analyses of each database.
"We would expect at most 8.07 excess cases of ventricular arrhythmia to be associated with azithromycin use per 100,000 person-years compared with nonuse of antibiotics," the researchers report.